Glucose dependent-insulinotropic polypeptide, also known as, gastric inhibitory polypeptide (hereinafter, abbreviated to GIP) is one of the gastrointestinal hormones belonging to a glucagon/secretin family. GIP, together with glucagon-like peptide 1 (GLP-1), is referred to as incretin and secreted from K cells present in the small intestine upon ingestion, and promotes the secretion of insulin by glucose in pancreatic β cells, thereby controlling the movement of nutrients in the living body upon ingestion. In addition, GIP is estimated to inhibit stomach motility and to stimulate intestinal secretion. However, its initially found inhibitory action on secretion of gastric acid is questionable at present. A GIP receptor gene is expressed widely not only in pancreatic β cells and adipocytes but also in other cells, and it is thus estimated that GIP also act in other tissues, which is however not fully elucidated.
Obesity is a lifestyle-related disease increasing due to westernization of the dietary habits of the Japanese at present, and is a risk factor of lifestyle-related diseases such as fatty liver, diabetes, gout, hypertension and arteriosclerosis. Medically, obesity is recognized as a morbid state of abnormal accumulation of fat resulting from relatively excessive ingestion of calories caused by hereditary and environmental factors, and is regarded as a subject of medical treatment. Treatment of obesity is carried out by combination of dietary cure and exercise cure, and an appetite inhibitor is rarely used. In Japan, a clinically used remedy for preventing or ameliorating obesity is only madindol (sanolex), while studies on other remedies such as β3 adrenaline receptor agonists, central nervous agonists, inhibitors of digestion and absorption, inhibitors of lipid synthesis, and leptin are advancing.
Madindol, which is commercially available as an adjunctive agent in dietary/exercise cures for severe obesity, is an appetite suppressant that act on the central nervous system, but its clinical effect is insufficient, and owing to the action on the central nervous system, the problem of dependence is pointed out. Other appetite suppressants working in the central nervous system, which act by different mechanisms, have been developed, but side effects in the central nervous system, such as increase in blood pressure, anxiety and headache, are worried about. A lipase inhibitor (orlistat), working mainly for inhibiting absorption of lipid and the like, is not reported to have severe side effects, but side effects such as fatty stools and flatus are reported. Leptin was expected as a promising candidate for a therapeutic agent for obesity because of its inhibitory effect on increase in body weight by decreasing food intake and accelerating energy consumption, but clinical tests revealed that the therapeutic effect is limited. β3-Receptor agonists are also expected as anti-obesity medicines, but their high receptor selectivity is essential, and side effects on the heart and the like are worried about if the selectivity is insufficient.
As described above, anti-obesity medicines based on various working mechanisms are commercially available or under development, but there are no medicines having both sufficient inhibitory effect on body weight gain and safety.
There are few studies on the relationship between GIP and obesity, but in recent years, the relationship is being elucidated. That is, a high-fat diet loading test on GIP receptor gene-deficient mice, conducted in a process for investigating the functions of GIP, revealed that obesity, occurring in wild-type mice, was inhibited in the GIP receptor gene-deficient mice (K. Miyawaki et al., “Inhibition of GIP Signaling Prevents Obesity”, abstract #335-PP, the 61st Scientific Sessions of American Diabetes Association (2001)). When these GIP receptor gene-deficient mice were given conventional diet, the mice showed no difference from the wild-type mice in body weight change, thus suggesting that inhibiting the functions of GIP causes no adverse influence. It is also revealed that even in ob/ob mice, which are animals with hereditary obesity, obesity can be inhibited by making the mice deficient in the GIP receptor gene (see WO 01/87341).
From the foregoing, GIP was suggested to cause obesity with a new mechanism not proposed up to now, and compounds inhibiting the functions of GIP, for example antagonists of GIP receptors and inhibitors of GIP production, are promising as safe medicines having an anti-obesity effect.
Examples of the compounds inhibiting the functions of GIP may include GIP receptor antagonists such as GIP(6–30) —NH2 (Regulatory Peptide, Vol. 69, pp. 151–154, 1997) and GIP(7–30) —NH2 (Am. J. Physiol., 1999, Vol. 276, pp. E1049–54). However, these compounds are long-chain peptides and problematic in oral absorptivity and stability in blood, and are not suitable as anti-obesity agents. Besides these peptides, 3-bromo-5-methyl-2-phenylpyrazolo[1,5-a]pyrimidin-7-ol disclosed in WO 01/87341 is mentioned as a low-molecular compound inhibiting the functions of GIP, but its inhibitory activity is weak because its IC50 is about 40 μM. As described above, a low-molecular compound strongly inhibiting the functions of GIP is still not known.
GIP, together with glucagon and GLP-1, is known as gastrointestinal hormone belonging to the glucagon/secretin family, and their primary amino acid sequences are highly homologous. The primary sequences of their receptor proteins are also highly homologous. However, whether or not a low-molecular inhibitor of functions of glucagon, for example, acts as an inhibitor of functions of GIP and/or GLP-1 is not evident. For example, L-168,049 known as a very potent antagonist of glucagon is considerably poor in an ability to bind to receptor for GLP-1, having the highest homology to glucagon (Margaret A. Cascieri et al., J. Biol. Chem., Vol. 274(13), 8694–8697 (1999)). The ability of L-168,049 to bind to GIP receptor is not described therein. Compounds disclosed in WO 02/00612 have a strong antagonistic activity on receptors of only glucagon, as compared with GIP and GLP-1. Further, compounds exhibiting a glucagon antagonistic activity, disclosed in WO 00/39088, are not known to have an antagonistic activity on GIP receptor. It is thus not possible to predict whether the antagonists for glucagon, belonging to the same family, act as GIP antagonists.
It is an object of the present invention to provide a low-molecular inhibitor of GIP functions and, further, an agent for preventing/ameliorating obesity in a new mechanism based on inhibition of GIP functions.